Atherosclerosis is characterized by the build up of fat, cholesterol, and immune cells in the walls of arteries to form plaques. When the surface of a plaque weakens, it can become unstable and rupture producing a heart attack or stroke, the leading cause of death in the US. The long-term goal of this research is to identify cellular mechanisms modulating atherosclerotic plaque in order to find new ways of treating atherosclerosis. Cannabinoids are compounds related to the active ingredient in marijuana and exert their effects by binding to cell surface receptors called cannabinoid receptors. Recent studies have shown cannabinoid receptors are dysregulated in a number of different inflammatory conditions, including atherosclerosis. Mice lacking the type 2 cannabinoid receptor, known as CB2, develop atherosclerotic plaques with evidence of reduced stability. However, the precise functions of CB2 in different stages of atherosclerosis are unclear, and it is unknown if targeting CB2 will trigger disease progression or provide a protective effect on plaque stability. The overall objectives of this research are to define the functions of CB2 in atherosclerosis and determine the effects of selectively targeting CB2 on plaques in atherosclerosis-prone mice. The central hypothesis is that macrophage CB2- dependent processes affect plaque stability, and that administration of CB2-selective compounds will provide beneficial effects on atherosclerosis. To test this hypothesis we propose the following specific aims: 1) Identify CB2-dependent effects on lesion stability in atherosclerosis-prone mice, 2) Identify CB2-dependent effects on atherosclerotic lesion calcification mechanisms in mice, and 3) Identify the cell types contributing to CB2-dependent effects on atherosclerosis in mice. Each aim will be tested using atherosclerosis-prone mice which lack CB2 and by treating atherosclerosis-prone mice with compounds to selectively activate or inhibit CB2. This research is innovative because no data currently exist regarding the effects of CB2 in advanced atherosclerosis or how CB2-selective compounds will affect atherosclerosis. Ultimately, the knowledge gained from this project will advance the field of atherosclerosis research by providing information necessary to determine if CB2 is a viable target for the design of potentially new therapies to treat atherosclerosis in humans.